Nitisinone

5 WARNINGS AND PRECAUTIONS Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques : Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine, which at levels above 500 micromol/L can result in symptoms, intellectual disability and developmental delay or painful hyperkeratotic plaques on the soles and palms; do not adjust nitisinone dosage in order to lower the plasma tyrosine concentration. Obtain slit-lamp examination prior to treatment, regularly during treatment; Reexamine patients if symptoms develop or tyrosine levels are > 500 micromol/L. Assess plasma tyrosine levels in patients with an abrupt change in neurologic status. (5.1) Leukopenia and Severe Thrombocytopenia : Monitor platelet and white blood cell counts. (5.2) 5.1 Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology (12.1)] . Therefore, treatment with nitisinone may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on nitisinone treatment. Do not adjust nitisinone dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following: Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with nitisinone [see Adverse Reactions (6.1)] . In a clinical study in a non HT-1 population without dietary restriction and reported tyrosine levels >500 micromol/L both symptomatic and asymptomatic keratopathies have been observed. Therefore, perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating nitisinone treatment and regularly thereafter. Patients who develop photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning of the eyes or tyrosine levels are >500 micromol/L during treatment with nitisinone should undergo slit-lamp reexamination and immediate measurement of the plasma tyrosine concentration. Variable degrees of intellectual disability and developmental delay. In patients treated with nitisinone who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels. Painful hyperkeratotic plaques on the soles and palms In patients with HT-1 treated with dietary restrictions and nitisinone who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. 5.2 Leukopenia and Severe Thrombocytopenia In clinical trials, patients treated with nitisinone and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions (6.1)] . No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during nitisinone therapy.

6 ADVERSE REACTIONS Most common adverse reactions (>1%) are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of nitisinone is 0.5 mg/kg twice daily [see Dosage and Administration (2.1)]. Median duration of treatment was 22 months (range 0.1 to 80 months). The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)] . Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%). The most common adverse reactions reported in the clinical trial are summarized in Table 1. TABLE 1 Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone* Elevated tyrosine levels Leukopenia Thrombocytopenia Conjunctivitis Corneal opacity Keratitis Photophobia Eye pain Blepharitis Cataracts Granulocytopenia Epistaxis Pruritus Exfoliative dermatitis Dry skin Maculopapular rash Alopecia >10% 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% *reported in at least 1% of patients Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

<table width="629.622" cellspacing="0" cellpadding="0"><colgroup><col width="49.4296577946768%"/><col width="50.5703422053232%"/></colgroup><tbody><tr styleCode="Botrule First"><td styleCode="Lrule Rrule" colspan="2" align="center" valign="top"><content styleCode="bold">TABLE 1</content> <content styleCode="bold">Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone*</content></td></tr><tr><td styleCode="Lrule Rrule" valign="top">Elevated tyrosine levels Leukopenia Thrombocytopenia Conjunctivitis Corneal opacity Keratitis Photophobia Eye pain Blepharitis Cataracts Granulocytopenia Epistaxis Pruritus Exfoliative dermatitis Dry skin Maculopapular rash Alopecia</td><td styleCode="Rrule" align="center" valign="top">&gt;10% 3% 3% 2% 2% 2% 2% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1%</td></tr></tbody></table>